Sphingosine-1-phosphate (S1P) is a natural metabolite of sphingolipids, which comprise cell plasma membranes. Aside from its role in intracellular signaling, S1P is also released and acts in an autocrine or paracrine fashion on a family of G-protein coupled receptors (GPCRs): Sphingosine-1 Receptors 1-5 (S1P1-S1P5). S1P signaling has been linked to a variety of cellular processes including cell motility, invasion, angiogenesis, vascular maturation and lymphocyte trafficking. Recently, a modulator of S1P1 and S1P3-S1P5, fingolimod (also known as FTY-720 or Gilenya), has been found to be an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Fingolimod promotes the internalization of S1P1, reducing the aberrant lymphocyte trafficking common in MS. The surface expression level of S1P1 can be used as a marker of several diseases, including multiple sclerosis (MS), cancer, cardiovascular disease and rheumatoid arthritis. S1P1 levels can be assessed using imaging techniques such as positron emitting tomography (PET), which uses radioisotope labeled ligands that bind to a target and release gamma rays that can be detected for localization and quantification.
Given the association between S1P1 expression and signaling in various disease states, there is a need for new compounds having high affinity and selectivity for the S1P1.